Tetrahydrocannabinol (THC) is the primary psychoactive component found in cannabis. When this compound enters the body, it is recognized as a foreign substance, known as a xenobiotic. The liver is the main organ responsible for processing and breaking down THC. This metabolic process transforms the original compound into metabolites, preparing THC for eventual removal from the body.
The Liver’s Role in Drug Metabolism
The liver processes foreign compounds using a two-step detoxification process called biotransformation. This system converts fat-soluble molecules, which the body struggles to excrete, into water-soluble forms that can be dissolved in urine or bile. The first stage, Phase I metabolism, introduces a reactive chemical group on the molecule’s structure, often through oxidation, reduction, or hydrolysis reactions.
Phase I relies on Cytochrome P450 (CYP450) enzymes, a superfamily of proteins embedded in liver cells. These enzymes use oxygen to chemically modify the xenobiotic, slightly increasing its water solubility. Phase II metabolism involves conjugation, where the liver attaches a large, highly water-soluble molecule, such as glucuronic acid, to the modified compound. This final step significantly increases the metabolite’s water solubility, ensuring efficient excretion.
The Specific Metabolic Pathway of THC
The breakdown of THC is a specific, multi-step process driven by the liver’s CYP450 enzymes. The primary enzymes responsible for this initial transformation are the Cytochrome P450 isozymes CYP2C9 and CYP3A4. These enzymes target the THC molecule through hydroxylation, which adds a hydroxyl group to its structure.
This first step converts THC into the major metabolite, 11-hydroxy-THC (11-OH-THC). 11-OH-THC is active and often considered more psychoactive and potent than the original THC molecule. This metabolite contributes significantly to the effects felt when cannabis is consumed orally, as the drug passes through the liver before entering the bloodstream.
The liver works to neutralize this active compound. Further oxidation, mediated by CYP enzymes like CYP2C9, quickly converts 11-OH-THC into the second metabolite, 11-nor-9-carboxy-THC (THC-COOH). THC-COOH is pharmacologically inactive. This highly lipid-soluble molecule is the compound stored in the body’s fat tissues.
What Happens to the Metabolites
Once the liver creates the inactive THC-COOH, the molecule is prepared for elimination through the Phase II conjugation process. The liver attaches a glucuronic acid molecule to the THC-COOH, creating a highly water-soluble conjugate. This conjugation allows the metabolite to be dissolved in bodily fluids and expelled from the system.
The primary route of elimination for these conjugated THC metabolites is through the feces, accounting for over 65% of the total excretion. The remaining metabolites are eliminated through the urine, typically making up about 20% to 35% of the total amount. The lipophilic nature of unconjugated THC-COOH means it is readily absorbed and stored in fat cells throughout the body.
Storage in fat cells allows cannabis metabolites to be detected long after the psychoactive effects have worn off. THC-COOH is slowly released from these fat stores back into the bloodstream, leading to a long elimination half-life. For chronic users, the half-life can be extended, sometimes remaining detectable in urine for weeks. Drug screening tests primarily look for the inactive THC-COOH metabolite, as its presence confirms past cannabis exposure.